Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


10393.pdf (6.94 MB)

ETD Abstract Container

Abstract Header

IRAK Family Kinases as Therapeutic Targets for Myelodysplastic Syndrome and Acute Myeloid Leukemia

Rhyasen, Garrett W
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406810785

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Innate immune signaling has an essential role in inflammation, and the dysregulation of signaling components within this pathway is increasingly being recognized as a mediator in cancer initiation and progression. The innate immune system is an evolutionarily conserved pathogen pattern recognition apparatus, which defends the host in a non-specific manner. Pathogens and cytokines signal to immune cells through the toll-like receptor (TLR) and interleukin-1 receptor (IL1R) superfamily. In order to mediate an inflammatory response, TLRs and IL1R require interleukin-1 associated receptor kinases (IRAKs). Herein, we demonstrate that IRAK1 is activated and overexpressed in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); two closely related hematologic malignancies. Furthermore, pharmacological (IRAK-Inh) and RNAi-mediated inhibition of IRAK1 is effective in eliminating disease-propagating cells. Integrated gene expression analysis revealed compensatory BCL2 upregulation following small-molecule IRAK1 inhibition. This proved to be a drugable vulnerability, as BCL2 inhibition potently synergized with IRAK-Inh to induce rapid cell death, even in IRAK-Inh-refractory cell lines. Importantly, suppression of IRAK1 signaling, through either RNAi or small-molecule inhibition, is tolerated in normal CD34+ cells, suggesting a potential therapeutic window for MDS and AML patients. To examine the effect of cancer-modifying therapies, like IRAK inhibition, we developed a novel xenograft model, utilizing an MDS-derived patient cell line, MDSL. Immunocompromised animals receiving MDSL xenografts developed progressive anemia and thrombocytopenia, thus recapitulating clinical features of the disease. These mice displayed rapid morbidity resulting from MDSL engraftment in bone marrow, spleen and peripheral blood. In this setting, both RNAi-mediated and small-molecule IRAK1 inhibition was effective in reducing MDSL cell burden, and provided a significant survival benefit. To broaden our findings, we examined the effect of IRAK inhibition in the context of FLT3-mutated AML. Mutations in the type III receptor tyrosine kinase, FLT3, occur in approximately 30% of AML patients and lead to constitutive downstream signaling activation, thus FLT3 is an attractive molecular-target. Herein we report the structure and activity of several dual IRAK and FLT3 small-molecule kinase inhibitors, which exhibit potent cytotoxicity against D835-mutant FLT3 and FLT3-ITD AML cells. Three of our tool compounds exhibit 4- to 1300-fold greater cellular activity than quizartinib, a FLT3 inhibitor undergoing clinical investigation. Thus combining FLT3 and IRAK pathway inhibition appears to be a promising therapeutic strategy for mutant-FLT3 AML. In sum, our findings reveal the dependency of MDS and AML on TLR/IL1R signaling, and validate IRAK kinases as important therapeutic targets.
Daniel Starczynowski, Ph.D. (Committee Chair)
Gang Huang, Ph.D. (Committee Member)
H. Leighton Grimes, Ph.D. (Committee Member)
Ashish R. Kumar, M.D. Ph.D. (Committee Member)
Maria Czyzyk-Krzeska, M.D. Ph.D. (Committee Member)
James Mulloy, Ph.D. (Committee Member)
131 p.
Cellular Biology
Cancer Biology; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Kinase inhibitors; Novel therapeutic targets; Cancer xenograft models

Recommended Citations

Citations

  • Rhyasen, G. W. (2014). IRAK Family Kinases as Therapeutic Targets for Myelodysplastic Syndrome and Acute Myeloid Leukemia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406810785

    APA Style (7th edition)

  • Rhyasen, Garrett. IRAK Family Kinases as Therapeutic Targets for Myelodysplastic Syndrome and Acute Myeloid Leukemia. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406810785.

    MLA Style (8th edition)

  • Rhyasen, Garrett. "IRAK Family Kinases as Therapeutic Targets for Myelodysplastic Syndrome and Acute Myeloid Leukemia." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406810785

    Chicago Manual of Style (17th edition)

ucin1406810785
1,530
© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.